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Pharmacology N929 > Anticoagulants, Antiplatelets, and Thrombolytics > Flashcards

Anticoagulants, Antiplatelets, and Thrombolytics Flashcards

1
Q

anticoagulants

A

prevent clot formation of extension of existing clot. does not break down clots

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2
Q

antiplatelets

A

reduce platelet aggregation on the surface of the platelet. does not break down clots

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3
Q

thrombolytics

A

converts endogenous plasminogen to the fibrinolytic enzyme plasmin to dissolve newly formed blood clots. does break down clots.

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4
Q

intrinsic anticoagulant mechanisms (4)

A

fibrinolysis
tissue factor plasminogen inhibitor (TFPI)
protein C system
serine protease inhibitors (SERPINs)

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5
Q

what is the main source of anticoagulation factors

A

capillary endothelium

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6
Q

prevention of blood coagulation outside of body (3)

A

siliconized containers (stored donated blood)
heparin in CPB or artificial kidney machines
citrate ion

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7
Q

tissue factor plasminogen inhibitor

A

a polypeptide produced by endothelial cells. acts as natural inhibitor of extrinsic pathway by inhibiting TF-VIIa complex

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8
Q

protein C pathway (APC) 4 key elements

A

coagulation propagation is inhibited by this pathway, consists of

  1. protein C
  2. thrombomodulin
  3. endothelial protein C receptor
  4. protein S
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9
Q

protein C

A

enzyme with potent anticoagulant, profibrinolytic and anti inflammatory properties. activated by thrombin to form activated protein C (APC) and acts by inhibiting activated factors V and VII (with protein S and phospholipids acting as cofactors)

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10
Q

thrombomodulin

A

transmembrane receptor on endothelial cells. prevents the formation of the clot in the undamaged endothelium by binding to the thrombin

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11
Q

endothelial protein C receptor

A

another transmembrane receptor that helps activation of protein C

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12
Q

protein S

A

vitamin K dependent glycoprotein, synthesized by endothelial cells and hepatocytes. activity is by virtue of free form while bound form acts as inhibitor of complement system and sup regulated in inflammatory states, which reduce protein S levels thus resulting in procoagulant state. it functions as a cofactors to APC in inactivation of FVa and FVIIIa

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13
Q 
SERPIN: antithrombin
binds to (which pathway?)
enhanced in
synthesized in
t1/2
A

(previously known at ATIII)
main inhibitor of thrombin
binds and inactivates thrombin, factor IIa, IXa, Xa, XIa and XIIa
enzymatic activity of AT is enhanced in presence of heparin and lovenox
endogenous AT synthesized in liver
plasma t1/2 2.5-3.8 days

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14
Q

SERPIN: antithrombin deficiency

A

hereditary AT deficiency estimated to be 1 in 2-5k

acquired deficiency ie prolonged heparin infusions >4-5 days decreased plasma AT activity by 50-60% of normal

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15
Q

citrate ion

A

prevents coagulation of PRBC’s or any blood outside of body
any substance that deionized calcium will prevent coagulation
negatively charged citrate ion combines with positively charged calcium in the blood to cause an un ionized calcium compound
after injection, citrate ion is removed by the liver and is polymerized into glucose or metabolized.
-if there is liver damage or massive transfusion, citrate ion may not be removed quickly enough, and this can greatly depress the level of calcium in the blood

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16
Q

anticoagulants (5 groups)

A 
vitamin K antagonists
unfractionated heparin
low MW heparin and fondaparinux
direct thrombin inhibitors
direct oral anticoagulants
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17
Q

coumadins MOA

A

vitamin K antagonists, results in hemostatically defective vitk dependent coagulation proteins (II, VII, IX, X or 2,7,9,10)
effect caused by competing with vitamin K for reactive sites in enzymatic processes for formation of prothrombin and other clotting factors, thereby blocking action of vitamin K
platelet activity not altered

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18
Q 
coumadin PK
absorption 
protein binding
elimination t1/2************
contraindications
metabolism
A

rapidly and completely absorbed
97% protein bound
long elimination half life of 24-36h after PO admin
dont use in parturient-teratogenic
metabolized to inactive metabolites that are conjugated and excreted in bile and urine

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19
Q 
coumadin use
dose
onset
duration of single dose
INR effects
measurement
A

effective in prevention of thromboembolisms
2.5-10mg PO, dose varies among patients
onset 3-4d
duration of single dose 2-4d
effects seen on INR in 8-12h due to depletion of factor VII, however full clinical effects are not appreciated for several days
measured by PT/INR

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20
Q

INR goals with coumadin: 2-3x normal range (5)

A 
afib
VTE tx
PE tx
prevention of VTE in high risk surgery
tissue heart valves
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21
Q

INR goals with coumadin: 2.5-3.5x normal range (3)

A

mechanical heart valve
prevention of recurrent MI
hx VTE with INR 2-3

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22
Q

coumadin management before minor surgery

A

discontinue 1-5 days preop for PT 20% within baseline. reinstitute regimen 1-7d postop

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23
Q

coumadin surgical management: immediate surgery (24-48h) or active bleeding

A

give vitamin K 2.5-20mg PO or 1-5mg IV at a rate of 1mg/min

PT to normal range within 4-24h

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24
Q

coumadin surgical management: emergency

A

FFP or 4 factor concentrate aka Kcentra

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25
Q

heparin endogenously, what exogenous heparin is usually a mixture of

A

naturally occurring polysaccharide that inhibits coagulation. heparin is released endogenously by mast cells and basophils.
mixture of glycosaminoglycans that produce anticoagulant effect by binding to and enhancing naturally occurring effects of antithrombin

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26
Q

why would heparin be a problem for those that do not consume animal products

A

heparin is derived from porcine intestine or bovine lung

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27
Q

Unfractionated heparin MOA

A

binds to antithrombin (antithrombin III). enhances the ability of antithrombin 1000 times to inactivate a number of coagulation enzymes.
functions as anticoagulant by accelerating normally occurring antithrombin induced neutralization of activated clotting factors
neutralized thrombin prevents conversion of fibrinogen to fibrin

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28
Q

Unfractionated Heparin MW, binding

A

large MW
only about 1/3 of administered heparin binds to antithrombin, and this fraction is responsible for its anticoagulant effect

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29
Q

United States Pharmacopoeia (USP) and heparin

A

USP defines 1 unit of activity as amount of heparin that maintains fluidity of 1mL of citrated plasma for one hour after re calcification. heparin must contain at least 120 USP units/mL
because commercial preparations vary in the number of USP units per mL, it is prescribed in units

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30
Q 
Unfractionated heparin PK
lipid solubility
population you can use it with
protein binding
DOA
monitoring
t1/2 prolongation
A

poor lipid solubility (large molecule), cannot cross lipid barriers in large amounts
safe in obstetrics since it does not cross placenta
circulates bound to plasma proteins
DOA 1.5-4h
most commonly monitored via biologic activity aka clotting time in seconds
decrease in body temp prolonged t1/2 so during bypasses or neurosurgery

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31
Q

how is injected heparin destroyed

A

the enzyme heparinase

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32
Q

dose-response relationship of heparin

A

100units/kg IV elimination t1/2 56min

400 units/kg IV elimination t1/2 152 min

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33
Q

lab tests used to monitor heparin (3)

A

aPTT: expect 1.5-2.5 times pre drug value (30-35s)
ACT: baseline, 3-5 min post admin, 30m-1h intervals post admin. may need to redose to keep ACT up
HEPSTEM

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34
Q

clinical uses of heparin (7) and ACT’s for: vascular or non CBP cases, interventional aneurysm clipping/coiling, CPB

A

SQ VTE and PE prophylaxis: ERAS cases, ortho cases, post MI, hemodialysis
warfarin bridge
vascular or non CBP cases vary ACT >200-300 seconds
interventional aneyurysm clipping/coiling >250 seconds
CPB- act> 400-480 seconds (inadequate <180)

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35
Q

heparin dosing example: prophylaxis for thromboembolism

A

5000 units SQ q8-12h TBW

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36
Q

heparin dosing example: tx of thromboembolism

A

5000 units IV TBW followed by continuous infusion for goal PTT 1.5-2.5 times control value

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37
Q

heparin dosing example: cardiopulmonary bypass

A

400 units/kg IV TBW

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38
Q

heparin dosing example: vascular interventions

A

100-150units/kg IV TBW

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39
Q

heparin SE (8)

A 
hemorrhage, hematomas
thrombocytopenia, HIT
allergic reaction
hypotension with large doses
altered protein binding
chronic exposure can progress to reduction of antithrombin activity
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40
Q

intraspinal hematoma incidence and patients with increased likelihood of this occurring (5)

A

incidence .1 per 100,000 patients per year
-more likely to occur in anti coagulated or thrombocytopenia patients, patients with neoplastic disease, liver disease, alcoholism

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41
Q

IV heparin and neuraxial anesthesia

A

1 hour delay between needle placement and heparin administration
catheter should be removed 1 hour before heparin administration and 2-4h after last heparin dose
monitor PTT or ACT

42
Q

HIT definition and clinical confirmation

A

heparin dependent antibodies that aggregate platelets and leads to consumption which produces thrombocytopenia
clinically confirmed with laboratory tests for antibodies

43
Q

Mild or type 1 HIT

A

30-40% of heparin treated patients get this.
non immune mediated
PLT count <100,000cells/mm^3
typically presents 3-15 days after initiation of therapy

44
Q

severe or type II HIT

A

.5-6% of heparin treated patients get this
immune mediated
plt count <50,000 cells/mm^3
typically presents 6-10 days after initiation of therapy

45
Q

heparin allergic reactions and 3 sx

A

since heparin is obtained from animal tissues, caution should be used in patients with preexisting allergy history. fever, urticaria, hemodynamic changes can be found with a true allergic reaction

46
Q

antithrombin deficiency and heparin

A

patients with antithrombin deficiency will have resistance to heparin
no antithrombin=nothing for heparin to bind to
occurs in up to 22% of patients undergoing cardiac surgery
patient who received intermittent or continuous heparin therapy may manifest a progressive, paradoxical reduction of antithrombin
this decrease in antithrombin may paradoxically increase thrombotic tendency. estrogen containing contraceptives also decrease antithrombins ability to inhibit Xa

47
Q

treatment to restore normal antithrombin values when heparin resistance is secondary to antithrombin deficiency

A

2-4units FFP in adults

antithrombin concentrate

48
Q

heparin reversal and dose

A

protamine for heparin neutralization
1-1.5mg for each 100units of heparin administered
(take into account how long case has been and metabolized heparin)

49
Q

LMWH derived from

A

standard commercial grade unfractionated heparin by chemical depolymerization to yield fragments approx 1/3 the size of heparin. depolymerization results in changes to anticoagulant profile, PK and effects on platelet function

50
Q

Enoxaparin (Lovenox) MOA and dose example

A

binds to and accelerates antithrombin.
inhibits factors Xa and IIa (Xa>IIa)
factor Xa catalyzes the conversion of prothrombin to thrombin, so enoxaparins inhibition of this process results in decreased thrombin activity and prevention of fibrin clot formation. (smaller, less protein binding)
DVT prophylaxis dose example: 30mg SQ q12h

51
Q

Enoxaparin advantages

A

reduced dosing frequency, lack of need for monitoring
more predictable PK response
fewer effects on platelet function
reduced risk for HIT

52
Q

Enoxaparin disadvantages

A

more expensive
surgery must be delayed for 12 hours after last dose
protamine only neutralizes about 65% of anti factor X activity. a more complete reversal must be with FFP but still dont have a great reversal for LMWH

53
Q

Direct Oral Anticoagulants (DOAC’s)
uses
examples

A 
alternatives to warfarin (tx of VTE, prevention of embolic CVA, prophylaxis in patients undergoing surgery
direct thrombin (IIa) inhibitor: dabigatran
direct factor Xa inhibitor: rivaroxaban, apixaban, edoxaban
54
Q

DOAC advantages

A

rapid onset with peak effect 2-4h
predictable pharmacodynamics
minimal drug interactions
no required routine lab monitoring

55
Q

Dabigatran (Pradaxa)
type of drug
elimination

A

direct thrombin IIa inhibitor
“the renal elimination one”. decrease dose in renal patients
t1/2 12 hours unless reduced renal function

56
Q

Dabigatran monitoring

A

challenging to monitor- coagulation assay
dilute thrombin time
aPTT
ROTEM

57
Q

Dabigatran reversal:

A

Idarucizumab (Praxbind)
specific for this drug
binds to dabigatran with 350x higher affinity than thrombin
t1/2 45 minutes

58
Q

direct factor Xa inhibitors (3)

A

rivaroxaban (Xarelto)
Apixaban (Eliquis)
Edoxaban (Savaysa)

59
Q

Direct factor Xa inhibitors:
metabolism
monitoring

A

metabolism: mostly hepatic, 65-70%
monitoring: still challenging. coagulation assay or anti Xa, which is not widely available
ROTEM is not sensitive
PT can be helpful for rivaroxaban only

60
Q

general management of DOAC treated patients undergoing surgery: minimal bleeding risk

A

likely safe to undergo with no DOAC interruptions

ex) minor dental procedures, cataracts, skin biopsies

61
Q

general management of DOAC treated patients undergoing surgery: low bleeding risk procedures

A

generally recommended to stop DOAC 24 h prior to elective surgery
ex hernia repair

62
Q

general management of DOAC treated patients undergoing surgery: high bleeding risk

A

generally recommended interruption of DOAC therapy 48h prior to elected surgery.
longer interruption interval necessary for dabigatran and impaired renal function
ex) cardiac, intracranial surgeries

63
Q

antiplatelets agent classes (3)

A

cyclooxygenase inhibitors (asa, NSAIDS)
P2Y12 receptor antagonists
glycoprotein IIB/IIIA inhibitors

64
Q

antiplatelets MOA and indications

A

suppress platelet function (inhibit platelet aggregation) for the prevention of thrombosis
antiplatelet therapy is indicated for patients at risk for CVA’s, MI, or other vascular thrombosis complications.

65
Q

mechanisms for platelet suppression include

A

COX inhibition
TXA2 inhibition
ADP receptor antagonism
GP IIb/IIIa receptor antagonism

66
Q

aspirin MOA and dose

A

exerts antithrombotic effects by inhibiting platelet aggregation. inhibits thromboxane A2 synthesis by interfering with activity of cyclooxyrgenase 1 and 2 enzymes and subsequent release of ADP by platelets and their aggregation
effects are irreversible and last the life of the platelet
dose: 81-325mg

67
Q

ASA and cyclooxygenase

A

cyclooxyrgenase is nonfunctional because acetyl group of ASA causes acetylation of cyclooxygenase. cyclooxygenase is the rate limiting enzyme in the conversion of arachidonic acid to thromboxane A2

68
Q

NSAIDS (3 drugs)

A

ketorlac
naprosyn
ibuprofen

69
Q

NSAIDS MOA and DOA

A 
same MOA as aspirin, nonselective COX inhibitors. 
reversible depress thromboxane A2 and production by platelets
more temporary (24-48h) and are often held prior to surgery
70
Q

management of ASA in the preoperative period: primary prophylaxis

A

for hyperlipidemia in the absence of established CV disease
ASA 81-325mg
probably hold but at discretion of surgeon

71
Q

management of ASA in preop period: secondary prophylaxis

A

for afib, previous MI, stent. probably will continue but assessment and talking with surgeon will help.

72
Q

hold asa in these specific circumstances:

A

intracranial, middle ear, posterior eye or intramedullary spine surgery, possibly in prostate surgery. decision should be documented

73
Q

P2Y12 receptor antagonist examples (2)

A

clopidogrel

ticagrelor

74
Q

P2Y12 receptor antagonist MOA
discontinue window
platelet function studies
reversal

A

inhibitors of platelet activator and aggregation through irreversible binding of its active metabolite to P2Y12 class of ADP receptors on platelets

  • must dc 7 days prior to surgery
  • platelet function studies are unreliable for clopidogrel, but inhibit of the P2Y12 ADP receptor is available
  • platelet transfusion is useful for emergent surgery and restoring hemostasis
75
Q

Clopidogrel

A

pro drug and must be metabolized by CYP450 enzymes to produce active metabolite that inhibits platelet aggregation for the life of the platelet

76
Q

Ticagrelor

A

does not need hepatic activation and might work better for patients with genetic variants. recent PLATO trial suggests that ticagrelor has better mortality rates in treating patients with ACS (v clopidogrel)

77
Q

indications for P2Y12 receptor antagonists

A

secondary prevention of MI, CVA
Acute coronary stenting
acute coronary syndrome
peripheral artery disease

78
Q

P2Y12 and PCI/stents

A

PCI causes endothelial and medial damage that heals by neointimal formation, usually within 2-6 weeks with bare metal stents. however, with drug eluding stents, re endothelialization and neointimal healing are delayed, keeping stent struts exposed, which causes platelet aggregation and thrombus formation.
as a general approach, elective surgical procedures should be delayed by at least 6 weeks after BMS and 6 months after DES placement.

79
Q 
ASA
secondary prevention and reduced mortality
withdrawal consideratons
synergistic drug
periop ACS
A
  • secondary prevention with ASA reduces mortality up to 30% in high risk groups
  • withdrawal of ASA in patients with CAD is associated with 2-4x increase in death/MI
  • ASA and P2Y12 receptor antagonists act synergistically
  • 10% of ACS in the perioperative period are precipitated by preop cessation of ASA
80
Q

stents and high risk

A

patients with stents are at a high risk of thrombotic events especially in first 3 months after insertion

81
Q

Platelet Glycoprotein IIb/IIIA antagonists MOA, uses

A

act at corresponding fibrinogen receptor that is important for platelet aggregation
blocks fibrinogen which is final common pathway of platelet aggregation
utilized in ACS, angioplasty failures, and stent thrombosis
can inject this drug directly into thrombosis in IR

82
Q

Platelet Glycoprotein IIb/IIIa antagonist drug examples (3)

A

abciximab (ReoPro)
Tirofiban (Aggrastat)
Eptifibatide (Integrillin)

83
Q

Glycoprotein IIb/IIIa antagonist monitoring, t1/2, SE, reversal

A

effects can be monitored with ACT’s and reversible with the clarance of the drug
ACT maintained between 200-400 seconds
most of these agents are renally excreted and have half lives around 2.5h except abciximab which has 12 hour t1/2 and clinical effects lasting 48h
platelet counts should be monitored, and therapy discontinued if thrombocytopenia develops (<100,000 cells/mm3)
effects of these drugs can be reversed with platelet transfusions

84
Q

herbal anticoagulants (6)

A 
garlic
ginko
ginseng
black cohosh
fish oil
feverfew
85
Q

garlic

A

inhibits platelet aggregation, discontinue for 7d

86
Q

gingko

A

inhibits platelet activating factor, discontinue for 36h

87
Q

ginseng

A

inhibits platelet aggregation and lowers BG. check PT/PTT/glucose, d/c for 24 hours (preferably 7d)

88
Q

black cohosh

A

claims to be useful for menopausal symptoms. contains small amounts of anti inflammatory compounds, infusing salicylic acid

89
Q

fish oil

A

claims to prevent/treat atherosclerotic CV disease (800-1500mg/day). also used to decrease triglycerides (>4g/day). dose dependent bleeding risk increases with dose >3g/day

90
Q

feverfew

A

claims to prevent migraines. increases risk of bleeding because it individually inhibits platelet aggregation. has additive effects with other anti platelet drugs. also has additive effects with warfarin

91
Q

fibrinolysis

A

when blood clot is initially formed, it is a semi solid mass consisting of platelets and a fibrin mesh that traps WBC’s and plasma
the clot solidifies as platelets contract and squeeze out water

92
Q

plasminogen

A

serum protein that is absorbed into clot at its formation. cleaved into plasmin which breaks down fibrin and fibrinogen. tissue plasminogen activator and urokinase type plasminogen activators are released from capillary endothelium

93
Q

thrombolytics, fibrin specific (3)

A

alteplase (TPA)
reteplase
tenecteplase

94
Q

thrombolytics, non fibrin specific

A

streptokinase

95
Q

thrombolytics MOA

A

possess inherent fibrinolytic effects or enhances body fibrinolytic system by converting endogenous pro enzyme plasminogen to fibrinolytic enzyme plasmin. more capable of dissolving newly formed clots.

96
Q

what does plasmin break down

A

fibrin

97
Q

active form of plasminogen

A

plasmin

98
Q

uses of thrombolytics, risk, window of use

A

used to restore circulation through previously occluded vessel (STEMI, acute ischemic CV, acute massive PE)

  • bleeding most common risk
  • usually 6 hour window
99
Q

contraindications of thrombolytics

A

trauma, severe HTN, active bleeding, pregnancy

100
Q

alteplase
window of use
administration considerations
t1/2

A

fibrin specific thrombolytic drug synthesized by endothelial cells
limited to use in the first 3-6h of ischemic CVA
can be administered systemically or directly into embolism
short t1/2 (about 5 min) so usually bolus then do gtt

101
Q

streptokinase

A

protein produced by beta hemolytic streptococci
not an enzyme, instead noncovalently binds to plasminogen and converts it to plasminogen activator complex that acts on other plasminogen molecules to generate plasmin
t1/2 20 minutes
as a bacterial product, may stimulate antibody production and subsequent allergic reactions
least expensive of thrombolytic drugs, therefore used internationally.

102
Q

thrombolytic adverse effects

A 
bleeding
re thrombosis (anticoagulants such as heparin are usually co administered and continued after thrombolytic therapy)

Pharmacology N929 (11 decks)

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